2.1 Medical Need
Human cytomegalovirus (HCMV) is a ubiquitous beta-herpes virus that typically causes chronic latent, asymptomatic infection in healthy individuals, with overall age-adjusted CMV seroprevalence in the developed world of above 50% (Bate et al., Clin. Infect. Dis., 2010, 50(11):1439; La Rosa & Diamond, Future Virol., 2012, 7(3):279). However, in immunocompromised patients, especially transplant recipients, HIV-infected persons, and congenitally infected newborns, CMV causes significant morbidity and mortality and therefore poses an important public health problem.
HCMV infection is the most common cause of congenital viral infection in the developed world. Approximately 40,000 congenitally infected infants are born in the United States per year. Congenital CMV infection can result in a wide range of neurodevelopmental disabilities, and it presents the most common infectious cause of hearing loss in children. The large public health impact of HCMV is demonstrated by the fact that more children suffer from long-term sequelae as a result of congenital CMV infection than either Down syndrome or fetal alcohol syndrome (Cannon et al., BMC Public Health, 2005, 5:70).
In addition to its impact as a perinatal infection, HCMV is also an important cause of infectious complications in transplant patients, causing pneumonitis, hepatitis, gastrointestinal ulceration, retinitis and death. Although nowadays these severe forms of end organ disease can be prevented in most cases by the cost-intensive, routine use of preemptive therapy with antiviral drugs, late reactivation of CMV infection is still a problem. Furthermore, CMV triggers indirect effects such as graft rejection, accelerated atherosclerosis after heart or lung transplant or immunosuppression.
Moreover, CMV infection and/or reactivation are also significantly associated with mortality in HIV patients as well as in patients admitted to intensive care units.
2.2 HCMV Immunity and Vaccine Development
The significant public health impact of congenital CMV has led the US Institute of Medicine to rank development of a CMV vaccine as a top priority in its recent report “Vaccines for the 21st Century”. Although vaccine development efforts have been going on for several decades; so far there is no licensed CMV vaccine available. Development of an efficacious vaccine has been proven difficult as there are still critical gaps in the understanding of CMV epidemiology and transmission.
CMV rarely elicits disease in healthy immunocompetent hosts, where immunity against CMV provides some level of protection and plays an essential role in maintaining asymptomatic infection. However, the human immune system is unable to clear the infection and CMV usually establishes chronic infections that can persist lifelong despite host immunity. In contrast, uncontrolled CMV viremia and life-threatening symptoms readily occur after immunosuppression and in the immature host.
Several vaccine candidates based on different technologies have already been studied in clinical trials. Partial protection by vaccination has been demonstrated with both live-attenuated and glycoprotein vaccine candidates inducing CMV-specific antibody responses. Passive immunization with antibodies has also been shown to provide some protection. However, once latent infection has been established, strong induction of CMV-specific T cells seems to be necessary to control reactivation and disease.
2.3 HCMV Vaccine Antigens
Several data indicate that neutralizing antibodies inhibiting CMV entry into host cells play an important role for prevention of horizontal and vertical virus transmission. Studies based on neutralization of fibroblast infection have defined the major envelope glycoprotein B (gB) as one of the dominant targets of neutralizing antibodies. The inclusion of gB in a human CMV vaccine candidate is further supported by clinical phase II data showing that a subunit vaccine based on gB in combination with MF59 adjuvant is able to confer partial protection in seronegative women (Pass, J. Clin. Virol., 2009, 46(Suppl 4):573; Pass et al., N. Eng. J. Med., 2009, 360(12):1191).
Though vaccine candidates based on recombinant gB elicit high titers of neutralizing antibodies preventing HCMV infection, other HCMV antigens may elicit higher titers of antibodies that inhibit HCMV infection of particular cell types, such as epithelial and endothelial cells. A vaccine strategy for effective prevention of HCMV infection will likely depend on the ability to induce potent neutralizing antibodies inhibiting virus entry into various cell types. Recent studies have shown that a pentameric complex formed by the glycoproteins gH/gL (UL75/UL115), UL128, UL130, and UL131A is required for HCMV entry into epithelial and endothelial cells and is the target of potent neutralizing antibodies in HCMV-seropositive individuals (Ryckman et al., J. Virol., 2008, 82(1):60; Wang & Shenk, Proc. Natl. Acad. Sci. USA, 2005, 102:18153; Wussow, et al., J. Virol., 2013, 87(3):1322).
A potential vaccine antigen for the induction of protection against CMV disease mediated by cytotoxic T cells, is the tegument protein pp65 which is an immunodominant CD8+ T-cell antigen (Wills et al., J. Virol., 1996, 70(11):7569). pp65-specific CD8+ T-cell frequencies have been associated with immune control of CMV in transplant patients (Pipeling et al., J. Infect. Dis., 2011, 204(11):1663) and adaptive transfer of pp65-specific T cells appears to have therapeutic utility in hematopoietic stem cell transplant recipients (Peggs et al., Clin Infect Dis 2011, 52(1):49; Einsele et al., Blood, 2002, 99(11):3916; Micklethwaite et al., Blood, 2008, 112(10):3974). Taken together these findings suggest that a CMV vaccine designed to prevent CMV disease in transplant patients requires inclusion of pp65.